We developed a renewable mouse resource for genetic analysis of complex cardiovascular traits. The resource, which we term the Hybrid Mouse Diversity Panel (HMDP), consists of 100 selected inbred strains that have been largely sequenced and that exhibit great diversity in their responses to atherosclerosis. This resource can be used to map complex traits with excellent resolution and to perform pathway analysis using systems genetics. In Aim 1, we propose to exploit this resource for the analysis of arterial inflammation and intestinal lipid metabolism. We will examine higher order genetic interactions using pathway analysis and network modeling to identify novel mechanisms for atherosclerosis. We will also create and maintain a systems genetics database for the larger cardiovascular research community. In Aim 2, we will study in detail a novel regulatory pathway, involving the transcription factor Zhx2 that we previously identified in using a systems genetics approach. Mice carrying a naturally occurring deficiency of Zhx2 expression have a 10-fold to 20-fold reduction in lesion size, and bone marrow transplantation studies indicate that this effect is mediated largely by hematopoietic cells. The mutation does not affect levels of monocytes, but rather promotes macrophage apoptosis, likely involving the NF-?B pathway. We will identify the pathways perturbed by Zhx2 deficiency and examine macrophage survival and growth using in vivo labeling and parabiosis experiments.